Process for the preparation of high purity miglustat
Inventors
Shah, Shrenik K. • Kharatkar, Raju Mahadev • BHATT, Chiragkumar Anilkumar • Kevat, Jitendra Bhagwandas
Assignees
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Publication Number
US-9718777-B2
Publication Date
2017-08-01
Expiration Date
Abstract
A process for the preparation and isolation of crystalline miglustat without the use of a column chromatography or ion exchange purification. The crystalline miglustat has a high purity and a melting point of 128° C. and an endothermic peak is 133° C.
Core Innovation
The invention relates to an improved process for the preparation of crystalline miglustat of formula (I). The process produces miglustat by first preparing a salt form and then converting it to crystalline miglustat through treatment with an organic base and crystallization by addition of a second solvent. The process is presented as commercially viable and avoids traditional purification by ion-exchange chromatography and flash column chromatography.
In one aspect of the process, 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin hydrochloride of formula (V) is reacted with n-butyraldehyde and sodium cyanoborohydride in an organic solvent to prepare 2,3,4,6-tetra-O-benzyl-N-butyl-1-deoxynojirimycin hydrochloride of formula (VI). The intermediate is then reacted with hydrogen in the presence of 10% Pd/C and HCl to produce miglustat hydrochloric salt, after which the salt is dissolved in a first solvent and an organic base is added to enable crystallization of miglustat.
In another aspect, a solution of miglustat acid salt in a first solvent is treated with an organic base, optionally removing the first solvent, and then adding a second solvent to crystallize miglustat of formula (I). The process explicitly requires that no flash column chromatography or ion exchange column is used, and is supported by reported purity and impurity results including 5R undesired isomer impurity levels and thermal properties measured by DSC and characterized by FTIR.
Claims Coverage
The document contains two independent claims. Across these claims, the coverage centers on a salt-to-crystal workflow using treatment with an organic base followed by crystallization by addition of a second solvent, with explicit exclusion of flash column chromatography and ion exchange columns in the process.
No flash column chromatography or ion exchange column
A process for preparing crystalline miglustat wherein no flash column chromatography or ion exchange column is used in the process.
Salt treatment with organic base and crystallization by second solvent
Treating a solution of miglustat acid salt in a first solvent with an organic base, optionally removing the first solvent, and adding a second solvent to crystallize miglustat of formula (I).
Protected deoxynojirimycin hydrochloride to miglustat hydrochloric salt and base-induced crystallization
Reacting 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin hydrochloride of formula (V) with n-butyraldehyde and sodium cyanoborohydride to prepare 2,3,4,6-tetra-O-benzyl-N-butyl-1-deoxynojirimycin hydrochloride of formula (VI); reacting the formula (VI) intermediate with hydrogen in the presence of 10% Pd/C and HCl to produce miglustat hydrochloric salt; dissolving miglustat hydrochloric salt in a first solvent and adding an organic base; optionally removing the first solvent; and adding a second solvent to crystallize miglustat.
The independent-claim scope is directed to preparing crystalline miglustat through formation of a miglustat acid salt (including miglustat hydrochloric salt in one claim) followed by treatment with an organic base and crystallization by addition of a second solvent, while expressly excluding the use of flash column chromatography and ion exchange columns. Dependent claims further specify selectable organic bases and solvent sets for the treatment and crystallization steps.
Stated Advantages
Improved purity of crystalline miglustat, with purity reported as ≥99.5% by HPLC.
Low impurity levels, including control of 5R undesired isomer impurity (<0.2% or preferably <0.1% by HPLC).
Improved thermal properties as characterized by melting point and DSC endotherm (melting point reported as 128°C; DSC endothermic peak reported as 133°C).
Elimination of traditional purification approaches by ion-exchange chromatography and flash column chromatography.
Documented Applications
Gaucher's disease as an indicated context associated with miglustat as a glycosyltransferase inhibitor.
Use context as a glycosyltransferase inhibitor.
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